1. Field of the Invention
The present invention relates to a device and a method for applying a plurality of microdroplets onto a substrate and in particular to such a device and such a method which permit the simultaneous application of a plurality of microdroplets. The present invention specially refers to such devices and methods which are suitable for producing so-called biochips in the case of which a plurality of different analytes is applied to a substrate so as to detect different substances in an unknown sample.
The fact that the genomes of human beings, animals and plants are deciphered to an increasing extent provides a large number of new possibilities ranging from the diagnosis of genetically conditioned diseases to a much faster search for pharmaceutically interesting agents. The above-mentioned biochips will, for example, be used in the future for examining food with respect to a large number of possible, genetically modified components. In another field of use, such biochips can be used for determining the exact genetic defect in the case of genetically conditioned diseases so as to derive therefrom the ideal strategy for treating the disease.
The biochips which are suitable for such cases of use normally consist of a carrier material, i.e. a substrate, having applied thereto a large number of different substances in the form of a raster. Typical raster distances in the array are distances between 100 μm and 1,000 μm. Depending on the respective case of use, the large number of different sub-stances on a biochip, which are referred to as so-called analytes, ranges from a few different substances to a few 100,000 different substances per substrate. Each of these different analytes can be used for detecting a very specific substance in an unknown sample.
When an unknown sample fluid is applied to a biochip, reactions will occur in the case of specific analytes; these reactions can be detected with the aid of suitable methods, e.g. fluorescence detection. The number of different analytes on the biochip corresponds to the number of different components in the unknown sample fluid which can simultaneously by analyzed by the respective biochip. Such a biochip is a diagnostic tool with the aid of which an unknown sample can be examined with regard to a large number of constituents simultaneously and purposefully.
2. Description of Prior Art
For applying the analytes to a substrate in order to produce such a biochip, three fundamentally different methods are known for the time being. Depending on the number of biochips required and on the necessary number of analytes per chip, these methods are used alternatively.
The first method is referred to as “contact printing”, a bundle of steel capillaries filled with various analytes in the interior thereof being used for executing this method. This bundle of steel capillaries is stamped onto the substrate.
When the bundle is taken off, the analytes adhere to the substrate in the form of microdroplets. In the case of this method, the quality of the printed pattern is, however, strongly determined by the effect of capillary forces and depends therefore on a large number of critical parameters, e.g. the quality and the coating of the surface of the substrate, the exact geometry of the nozzle and, primarily, the media used. In addition, the method is very susceptible to contaminations of the substrate and of the nozzles. The method described here is suitable for use in cases where the number of analytes does not exceed a few hundred per substrate.
In a second method for producing biochips, the so-called “spotting”, so-called microdispensers are normally used, which, similar to an ink-jet printer, are capable of shooting individual microdroplets of a liquid onto a substrate in response to a respective control command. Such a method is referred to as “drop-on-demand”. Microdispensers of this kind are commercially available from some firms. The advantage of this method is to be seen in the fact that the analytes can be applied onto a substrate in a contactless manner, the influence of capillary forces being then irrelevant. An essential problem is, however, that it is very expensive and extremely difficult to arrange a large number of nozzles, which are each supplied with a different medium, in parallel or rather in an array. The limiting elements are here the actorics and the media logistics, which cannot be miniaturized to the extent desired.
A third method which is used at present for producing biochips is the so-called “synthesis method” in the case of which the analytes, which normally consist of a chain of linked nucleic acids, are chemically produced on the substrate, i.e. synthesized. For delimiting the spatial positions of the various analytes, methods are used which are known from the field of microelectronics, e.g. lithographic methods with masking techniques. This synthesis method is by far the most expensive one among the above-mentioned methods, but it can also be used for producing the greatest variety of analytes on a chip, in the order of magnitude of 100,000 different analytes per substrate.